Neuroglobin (Ngb) is one of the latest discovered globins that preferentially localize to neurons in vertebrate brain with a well-defined neuroprotective effect against a wide range of neurological disorders. However, the mechanism underlying the neuroprotective action of Ngb is still uncertain. Neurons are characterized by high metabolic activity and execute fast-paced energy-demanding processes. Moreover, neurons have poor nutrient storage and are particularly vulnerable to ischemic insult. Ngb expression is at the highest in neonatal brains which is coincident with the peak of lipogenesis in the brain and with the presence of glycogen in neural tissue. Interestingly, the higher Ngb expression in neonatal brain is associated with the long recognized ischemic tolerance in neonates. We have generated stable Ngb overexpression in a neuronal cell line and demonstrated that Ngb overexpression significantly inhibits AMPK signaling and increases cellular glycogen and lipid contents. Consistently, AMPK inhibition and glycogen synthase activation were found in cortical neurons of Ngb overexpression mice. These data provided the first evidence that Ngb might regulate neuron metabolism through AMPK signaling. Enhancing glycogenesis and lipogenesis in neuron could have distinct advantage for ATP production even under anaerobic condition. Our preliminary study further demonstrated that AMPK activation diminished the neuroprotection of Ngb overexpression. Given the well-established function of AMPK signaling in cellular metabolism, the high affinity of Ngb to oxygen, and that both Ngb and AMPK predominately express in neurons at CNS, it is plausible that Ngb might interact with AMPK signaling and play a critical role in neuron metabolism. Our central hypothesis is that Ngb overexpression increases nutrient storage capacity via inhibition of AMPK pathway and, thus, provides neuroprotective action against ischemic stroke. We will address the following two specific aims to test our central hypothesis. 1. Determine the role of Ngb overexpression in neuron metabolism and underlying mechanisms in physiological condition. 2. Determine the involvement of AMPK-mediated anabolic action in the neuroprotective effect of Ngb overexpression against ischemic stroke. The proposed studies are expected to have an important positive impact because they may identify novel therapeutic target that ultimately lead to the discovery of treatment for ischemic stroke.